Metastatic melanoma has few treatment options, and the current therapeutic standard of care is dacarbazine which is a highly cytotoxic drug with severe side effects including vomiting, headache and hair loss. Treatment with dacarbazine has a median progression-free enhancement of survival time of only 1.5 months. Riluzole (RilutekTM) is a non-toxic drug and the only FDA-approved treatment for amytrophic lateral sclerosis (ALS or Lou Gehrig's disease). We have recently shown that riluzole has dramatic anti-melanoma activity in vitro, in mice and in a Phase 0 human clinical trial. In the clinic, four of twelve melanoma patients showed significant clinical or radiologic evidence of Stage III and IV tumor response. These results, along with the mild side-effect profile that riluzole has shown among ALS patients, suggests that this drug has significant potential for use as an improved treatment for metastatic melanoma. However, the therapeutic utility of riluzole itself in ALS and eventually for melanoma is very constrained by rapid first-pass metabolism in the liver and an exceptionally high level of patient-to-patient variability in the extent of the Cyp1A2-mediated oxidative metabolism that is observed. We propose to solve this problem using a strategy in which prodrugs of riluzole having enhanced stability to hepatic metabolism are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process. Four different series of riluzole prodrugs will be prepared and evaluated for their chemical and enzymatic stability at differing pHs, in simulated gastric and intestinal fluid, in serum, and in rat and human liver microsomes. Prodrugs having a range of stability and cleavage profiles, but generally with projected t1/2 values of 1-4 hrs, will be evaluated for anti- melanoma activity using the same in vitro and murine melanoma assays which we have previously used to evaluate riluzole. Comparison of riluzole-, prodrug- and vehicle-treated animals will establish the advantage in efficacy (ED50) of individual prodrugs against melanoma. Full pharmacokinetic analysis will establish improvements in drug exposure, clearance and biological half-life. Our goal is to reposition riluzole-based therapy for the treatment of metastatic melanoma by the successful application of a prodrug strategy to solve the current drug metabolism and distribution limitations of riluzole itself. PUBLIC HEALTH RELEVANCE: Metastatic melanoma is a type of cancer having extremely low survival rates and very limited treatment options based on highly toxic chemotherapy agents. Riluzole is a non- toxic drug approved for amyotrophic lateral sclerosis (ALS). We have recently shown exciting preliminary results for riluzole treatment of metastatic melanoma in mice and human subjects. But because of differences in how individuals metabolize riluzole, it will be difficult for this drug to realize its full potential as a treatment for metastatic melanoma. In this application, we propose to design, synthesize and evaluate novel drug candidates which will release riluzole in a more predictable and longer-acting way, leading to improved therapies for metastatic melanoma.